Osmotic dispenser with collapsible supply container

ABSTRACT

An osmotic dispenser is comprised of (1) a water porous housing member confining (2) a first flexible bag of relatively impervious material containing an active agent and provided with active agent dispensing head, and (3) a second bag of controlled permeability to moisture containing a solution which exhibits an osmotic pressure gradient against water. The first and second bags are disposed within the housing member such that water permeates from the external environment through the housing and migrates by osmosis into the solution contained in the second bag which increases in volume thereby generating mechanical force on the first bag, which mechanical force in turn ejects the active agent out of the apparatus.

United States Patent 1191 Higuchi Sept. 25, 1973 OSMOTIC DISPENSER WITHCOLLAPSIBLE SUPPLY CONTAINER Takeru Higuchi, Lawrence, Kans.

52 us. c1. 128/260, 128/130, 128/213 51 110. C1 ..A61m 31/00 [58] 1 1010ofSearch ..128/127-131,l72,213,

OTHER PUBLICATIONS Australian Journal of Experimental Biology, Continu-'1 IV A IVIJv ous Injector," Vol. 33, pp. 415-420 by 5. Rose and J. F.Nelson.

Primary ExaminerRichard A. Gaudet Assistant Examiner-J. C. McGowanAttorney-Steven D. Goldby and Paul L. Sabatine 5 7 ABSTRACT An osmoticdispenser is comprised of (1) a water porous housing member confining(2) a first flexible bag of relatively impervious material containing anactive agent and provided with active agent dispensing head, and (3) asecond bag of controlled permeability to moisture containing a solutionwhich exhibits an 08- motic pressure gradient against water. The firstand second bags are disposed within the housing member such that waterpermeates from the external environment through the housing and migratesby osmosis into the solution contained in the second bag which increasesin volume thereby generating mechanical force on the first bag, whichmechanical force in turn ejects the active agent out of the apparatus.

18 Claims, 4 Drawing Figures I.. I I,

PATENTEI] SEP25I975 SHEET 2 OF 2 NM NM om OSMOTIC DISPENSER WITHCOLLAPSIBLE SUPPLY CONTAINER FIELD OF THE INVENTION This inventionrelates to an osmotic dispenser, and, more especially, to an osmoticdispenser capable of releasing to its outside environment concentrationsof active agent at an osmotically controlled rate over aprolonged periodof time.

DEFINITION OF TERMS The expression active agent" as used herein denotesany drug (as defined, infra); composition in any way affecting a'nybiological entity; substance having a nutrient or stimulating action, orgrowth inhibiting, destroying or any regulating action on plant growth,controlled or otherwise; substance to be assimulated by any organism,e.g., human being, animal, or lower order organism, for its nourishmentor for regulating its growth; substance exhibiting any of the aboveactivities to be directly applied to the habitat, surroundings orenvironment of any of the above organisms; and substance having anyother effect on any other environment, especially any aqueousenvironment.

Therefore, suitable active agents for use with the dispenser of thisinvention include, without limitation, those which are generally capableof:

l. Preventing, alleviating, treating or curing abnormal and pathologicalconditions of the living body by such means as destroying a parasiticorganism or limiting the effect of the disease or abnormality bychemically altering the physiology of the host or parasite;

2. Maintaining, increasing, decreasing, limiting or destroying-aphysiologic body or plant function, e.g., vitamin compositions, sexsterilants, fertility inhibitors, fertility promoters, growth promoters,and the like;

3. Diagnosing a physiological condition or state;

4. Controlling or protecting an environment or living body byattracting, disabling, inhibiting, killing, modifying, repelling orretarding an animal or microorganism, such as food and non-food baits,attractants and lures, biocides, pesticides, algicides, parasiticides,rodenticides, insecticides, fungicides and the like;

5. Preserving, disinfecting or sterilizing; and

6. Controlling or affecting generically an environment, as byintroducing a catalyst or metering a reactant into a reacting chemicalsystem, or by effecting any chemical process therein, such as afermentation, including propagation and/or attenuation of amicroorganism.

The terms environment," surroundings" and "habitat as used hereinaboveand herein denote any prospective situs for the osmotic dispenser ofthis invention, or at least for the water permeable membrane componentthereof, which is comprised of or will provide sufficient water forabsorption into the device to develop the needed osmotic pressure onwhich its motive force depends; and implicit in the foregoing definitionof active agent one that will develop its action in the presence of suchenvironment, surroundings or habitat, or one that will develop itsaction in a remote and/or another environment, which need not beaqueous, as hereinafter described and illustrated.

BACKGROUND OF THE INVENTION Many and varied compositions, products,appliances, depositors, applicators, dispensers, injectors and devicesare well known in the art in which the timing or spacing ofadministration or absorption of an active agent is regulated by thestructure or physical arrangement of elements so that a singleadministration provides a gradual but continuous or sustained feeding ofthe active agent to a system by slow or differential release. All ofsuch prior art devices and the like, however, are characterized by atleast one feature which adversely affects control over their rate ofsustained or differential release or which detracts from the practicalbenefits attendant the longterm continuous administration of variousactive agents both to humans, animals, and into other environments.

An osmotic dispenser too has been proposed which is capable ofdelivering drug solution at a relatively constant rate. See Rose andNelson, Austral. J. exp. Biol., 33, pp. 415 420 1955 The Rose et a1.injector consists of three compartments and a clamp to hold asemi-permeable membrane. The motive force of the injector depends on theosmotic pressure developed by a saturated aqueous solution of Congo redagainst water. This solution is contained in a partially collapsedrubber compartment and is separated from a second water compartment bythe semi-permeable cellophane membrane. The partially collapsed bag isplaced in a glass ampoule, with the drug compartment of the device beingdefined by the space between the Congo red bag and the glass ampoule.The ampoule is also provided with drug release means and when the drugcompartment is charged with a drug solution water will move by osmosisinto the Congo red solution, thus expanding the rubber compartment andproviding the mechanical force to eject the drug out of the apparatus.

The Rose et al device, however, has substantial inherent disadvantageswhich has prevented its wide acceptance by the medical community. In thefirst place, the use of a solution as the drug vehicle (1) will notpermit high concentration of drug to be embodied within the device; (2)such solutions exhibit the deleterious tendency to be released from thedevice by simple leaching; and (3) many chemical substances on prolongedstorage in a dissolved state undergo chemical deterioration. Thereference injector is moreover cumbersome in that it depends for itsmotive force on a separate water compartment rather than itsenvironment. In addition, the Roseet al device is essentially only aresearch or experimentation tool, is complex in construction and is atleast literally restricted to a Congo red solution to produce theosmotic driving force and to a cellophane osmotic membrane. See alsoRose and Ne]- son, Austral, J. exp. Biol., 33 pp. 411 414 (I955).

SUMMARY OF THE INVENTION Another object of this invention is to providean im-- proved osmotic dispenser which will permit high concentrationsof active agent to be embodied therein, and which high concentrations ofactive agent will neither exhibit the tendency to be leached from thedevice nor be decreased in potency by chemical breakdown.

Another object of this invention is to provide an osmotic active agentdispenser which depends for its motive force on its environment.

Still another object of this invention is to provide an osmoticdispenser, the osmotic membrane of which can be fabricated from many andvaried suitable materials, and which is capable of using a variety ofsolutions of osmotically effective solutes to produce the osmoticdriving force.

Yet another object of this invention is to provide an osmotic dispenserof simple design which will release active agent solution, or gel, orsemisolid active agent formulation, at a controlled rate over aprolonged period of time.

In attaining the objects of this invention, one feature resides in anosmotic dispenser comprised of a water permeable housing member,advantageously rigid or otherwise shape retaining in nature, saidhousing member confining a first flexible bag of relatively imperviousmaterial containing the active agent, advantageously a drug, preferablyin a gel, paste or other semisolid state (albeit a solution orconcentrated solution of active agent will sometimes suffice), and asecond bag of controlled permeability to moisture containing a solutionof an osmotically effective solute which exhibits an osmotic pressuregradient against water. The said first and second bags are disposedwithin the said water permeable housing member or porous shell such thatwater permeates from the environment through the porous shell or housingand migrates by osmosis into the solution contained in the second bag.The solution in the second bag increases in volume, exerting mechanicalforce on the active agent containing first bag, which mechanical forcein turn ejects the active agent out of the apparatus. For purposes ofpermitting the active agent to be squeezed out of the said firstflexible bag, same is provided with any suitable active agent releasemeans or dispensing head to the exterior of the device, e.g., longplastic tubing extending through the porous shell, or ductlike finetubule connections through the said outer shell.

Other objects, features and advantages of this invention will becomemore apparent from the following description when taken in conjunctionwith the accompanying drawings, and wherein like reference numerals areused to indicate like or equivalent parts.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a cross-sectional view of anosmotic dispenser of this invention;

FIG. 2 is a partial perspective view, partially in crosssection, of anintravaginal device (IVD) embodying the principles of the osmoticdispenser of FIG. 1;

FIG. 3 is a cross-sectional view of another osmotic dispenser of thisinvention; and

DETAILED DESCRIPTION OF THE INVENTION In one embodiment in accordancewith this invention, as illustrated in FIG. 1, an osmotic dispenser iscomprised of a water permeable housing member or porous shell 12,advantageously rigid or otherwise shape retaining in nature, said shellconfining in essentially parallel configuration a first flexible'bag 14or relatively impervious material and a second bag 16 of controlledpermeability to moisture. The said first flexible bag 14 contains theactive agent formulation 18, preferably in a gel, paste or othersemisolid state. The said second bag 16 contains a solution 20 of anosmotically effective solute which exhibits an osmotic pressure gradientagainst water. Initially, the bag 16 will advantageously contain asaturated aqueous solution of the solute and excess solid solute 22.Active agent release means 24 provides communication from the interiorof the bag 14 to the exterior of the device 10, in this instance thesaid means 24 being comprised of a narrowing neck in the porous shell 12and an outlet in the bag 14 concentrically secured to the narrowing neckin the said shell 12. The said bag 16 is of closed construction, isinitially partly collapsed within the shell 12, and when fully expandedwill substantially fill the said shell.

To use the osmotic active agent dispenser of FIG. 1 wherein the severalbags are arranged in parallel configuration, the device, when the activeagent is a drug or other agent for treating, etc., a living organism, iseither physically inserted or surgically implanted in the body of theorganism, typically a mammal, or is administered via thegastrointestinal tract. Once in place, the second bag 16 expands throughabsorption of water from either body tissues or body fluids through theporous shell 12 and through the wall members thereof in an effort toreach osmotic equilibrium, i.e., a transition from hypertonicity toisotonicity. As the confined bag 16 expands, it exerts pressure againstthe likewise confined drug containing first flexible bag 14. Suchpressure serves to squeeze out the drug content 18 of the bag 14 throughthe conduit 24. There is accordingly provided the gradual and controlledrelease of drug or similar agent directly to the body or affected organthereof over a prolonged period of time. Since approximately one-half ofthe bag 16 will be exposed to moisture, relatively rapid rates of drugrelease are attainable. Moreover, the use ofa semisolid drug vehiclewill reduce the tendency to release the drug, or any other active agentfor that matter, by leaching and will permit high concentrations thereofto be embodied within the device.

When the active agent is other than a drug or similar agent, or isintended for use other than in a living organism, the device isintroduced into the desired aqueous environment to produce the desiredeffect exactly as would be any of the known means for accomplishing alike result. And this is generally a mere physical insertion, such as byplacing a pesticide containing device in a river or stream, or acatalyst containing device in an aqueous reaction medium.

If desired, long flexible tubing of polythene or the like can beextended to the exterior of the device from the interior of the bag 14through the means defined by the narrowing neck of the shell 12 and theoutlet of the said bag 14 (see FIG. 3). In such manner the device can bedeposited at a site remote from the desired point of application andstill release its active agent contents through the tube directly tosaid point. This permitsplacement of the dispenser in an aqueousenvironment and release of the active agent into another environment,which need not be aqueous.

In FIG. 2 there is depicted an intravaginal device 30,

ring-shaped, which will dispense drug formulation at an essentiallyconstant rate based on the principle of the osmotic active agentdispenser of FIG. 1. This IVD embodiment is comprised of a ring-shaped,water permeable housing member or porous shell 12, again advantageouslyrigid or otherwise shape retaining in nature, and again confining inessentially parallel configuration a first flexible bag 14 of relativelyimpervious material and a second bag 16 of controlled permeability tomoisture. The bag 14 contains the drug 18, preferably in a gel, paste orother semisolid state, and the bag 16 contains the solution of theosmotically effective solute which exhibits an osmotic pressure gradientagainst water. Advantageously, the bag 16 contains a saturated solutionof the solute and excess solid solute 22, to ensure that the solutionremains saturated. At spaced intervals the bag 14 is provided withduct-like fine tubule connections through the outer shell 12 to permitrelease of the drug, illustrated in the drawing as release ports 24. Forexample, these fine tubine connections may take the form of a pluralityof hard capillary nipples on the bag 14 extending through the shell 12.

The IVD of FIG. 2 is used by placing same around the cervix employingthe usual techniques for positioning a cervical ring and, once in place,will release drug or a mixture of drugs at a closely regulated constantrate. Thus, it will be appreciated that mechanismwise the IVD of FIG. 2is functionally equivalent to the osmotic active agent dispenser of FIG.1.

Moreover, it will also be appreciated that, while in FIG. 2 there isdepicted an IVD bottomed on the principle of the osmotic active agentdispenser of FIG. 1, the said principle of the invention applies equallyas well to, for example, a device of a size, weight and shape as to beretained in the rumen of polygastric animals to release drug or similaragent thereto at a carefully controlled rate. A device of FIG. 1 type isadmirably suited for the continuous administration of the antibioticoxytetracycline to beef cattle from the rumen. Other variations on thebasic theme would be readily apparent to the skilled artisan. Althoughparticular configurations may be designed for specific body uses, eachof these configurations is applicable to use in other environments.

In FIG. 3 another osmotic active agent dispenser 40 is shown, similar tothat of FIG. 1, except that instead of the two separate bags arranged inmore or less parallel configuration, a concentric design is illustrated.

Such concentric design would be more effective and easier to fabricate.The embodiment of FIG. 3 provides for an interior, first flexible bag 14of relatively impervious material containing active agent 18 (or agents)either as a solution, concentrated solution, or preferably as asemisolid gel, paste or cream with active agent suspended or dissolvedtherein. The bag 14 is disposed within a second bag 16 of controlledpermeability to moisture, and the annular space therebetween is filledwith the solution 20 of the osmotically effective solute to provide theneeded osmotic pressure gradient or differential. This material, whichmust be nontoxic for drug or similar applications, preferably is presentpartly as an aqueous solution and partly as a solid 22. It can be seenthat, in use, as water is absorbed from the outside aqueous environmentthrough the porous shell and into the annular space, the contents of thebag 14 will be squeezed to the exterior of the device via the longplastic tubing 24, the length of which is directly proportional toreduction in the leaching effect heretofore mentioned.

In some instances, the device is of insufficient specific gravity tomaintain the placement at the desired location. In those instances, aweight or ballast can be placed in the device. For this purpose, one canuse iron plugs, iron ore tablets, brass plugs, or ceramic plugs.

For use in the rumen, the weight should be sufficient to provide aneffective specific gravity of greater than 1.5.-

Optionally, a separator of porous paper, fabric or the like can beplaced between the porous outer casing and the semi-permeable membranebag. This prevents the membrane from being punctured or drawn into tootight a contact with the casing, thereby assuring that the entiremembrane is exposed to the aqueous enviroment.

The impermeable bag 14 of the osmotic dispensers of the Figures of thedrawing containing the active agent composition should be substantiallyimpermeable both to water, and the other elements of the environment onwhich a device of such type is intended to be placed, the osmoticallyeffective solute, and components of the active agent composition.Typical materials for use as the impermeable bag include polyethylene,polyethylene terephthalate (Mylar), plasticized polyvinyl chloride,metal-foil polyethylene laminates, neoprene rubber, natural gum rubber,and Pliofilm (rubber hydrochloride). These materials are additionallyflexible, insoluble and chemically compatible with the active agenttherein, and, in the instance of providing a drug or like depot withinthe body of a living organism, are biologically inert, non-irritating tobody tissues and non-allergenic.

The membrane or second bag 16 can be formed from a wide variety ofmaterials permeable or semipermeable to solvent (water) but not tosolute, i.e., those suitable for the construction of an osmotic cell.For best results, the membrane should be substantially impermeable topassage of the osmotically effective solute so as to prevent loss of thesolute. Typical membranes are isotropic membranes such as unplasticizedcellulose acetate, plasticized celluloseaccetate, reinforced celluloseacetate, cellulose diand triacetate, ethyl cellulose; anisotropicreverse osmosis membranes which typically are made of cellulose acetate;silicone rubbers, polyurethanes, natural rubber, and hydrolyzedethylene/vinyl acetate copolymers. Isotropic membranes have less waterpermeability than do the anisotropic membranes. Also, with both types ofmembranes, increasing the acetate content of the cellulose acetatepolymer decreases the water permeability. In one specific embodiment,the membrane used was an isotropic cellulose acetate membrane, with noplasticizer, having an acetate substitution of 2.4, being 3 mils thick,and passing water at the rate of mg/cm per day against a saturatedsolution of magnesium sulphate at 39 C. These membranes too areinsoluble, and chemically compatible with the salt solution and excesssolute therein and the material in the annular space between the twobags (FIG. 3). For drug depot applications as previously described samealso are biologically inert, non-irritating to body tissues andnon-allergenic. For devices designed to deliver active agents relativelyrapidly for a limited period, membranes of controlled high waterpermeability are indicated: membranes of lower water permeability areused to provide slower and more prolonged delivery. At least in theembodiment of FIG. 1 where mechanical force is exerted by expansion ofthe bag 16, the membrane used should be flexible at least to the extentof permitting such expansion and the transmission of such mechanicalforce. This is unnecessary but acceptable in the embodiment of FIG. 3;for example, the bag 16 can be laminated at least in part to the porousshell.

The porous casing too is insoluble and can be formed of perforatedpolystyrene, perforated polyethylene, perforated polypropylene,perforated polyvinyl chloride, perforated polymethylmethacrylate, etc.,perforated sheet metal (e.g., aluminum, copper, steel, etc.), perforatedgalvanized pipe, perforated reinforced epoxy resin, metallic screen,sintered brass tubing, porous styrene/acrylonitrile copolymer, poroussintered polyethylene, or the like. It is not intended that the porouscasing or pump body act as a barrier to the transport of water. Again,for drug depot applications the same is advantageously biologicallyinert, non-irritating to body tissues and non-allergenic. In theembodiment of FIG. 2 the ring-shaped shell 12 is advantageously ofporous, hard plastic material, preferably of smooth exterior finish toreduce irritation. It will be appreciated that the said porous casing orshell need be rigid or otherwise shape retaining only to the extent ofproviding sufficient confinement for the two bags such that as oneincreases in volume the requisite corresponding pressure or force foractive agent ejection is transmitted to or generated against the other.It will thus also be appreciated that it is within the scope of thisinvention to provide an osmotic dispenser devoid of the said casingmember, as illustrated in FIG. 4, so long as the bags are so constructedand physically disposed relative to each other to permit of theaforesaid pressure generation and transmission, as, for example, a shaperetaining balloon divided into the two bags or compartments by means ofa flexible diaphragm. In this embodiment the active agent half of theballoon would be provided with a suitable dispensing head and the otherhalf would contain the solution of the osmotically effective solute andwould be fabricated at least in part from semipermeable materials.

Many other materials including those which are biologically acceptableare suitable for fabrication of the several component parts of thedevice of this invention. While the said several component parts of thedevice of the invention have previously been described as beinginsoluble under the conditions and in the environment of intended use,it is also within the scope of the invention that such materials beinsoluble only during the period of said intended use; thereafterdissolving away in the environment of the device. Thus, a dispenser ishere contemplated which is unaffected by its environment,solubility-wise, at the situs of use, or which is only slightly solubleduring the period of intended use, such that once its active agentcontent has been discharged it will then dissolve or erode away leavingno objectionable residue or empty container at the said situs of use.

It is further within the scope of the invention to optionally providethe subject dispenser with a selfcontained water supply or separatewater compartment, as in the first mentioned Rose and Nelsonpublication, supra.

The relative thicknesses of the various membranes comprising the severalbags of the invention, as well as the relative thickness of the porousshell can vary widely and are not limitations on the invention.Typically, however, the flexible active agent containing bag has a wallthickness of 0.5 to 50 mils and the water permeable membrane bag has awall thickness of l to mils.

One specific embodiment of a dispenser fabricated in accordance with thedesign illustrated in FIG. 1, fitted with a 2 mils thick flexible activeagent bag 14 and a 3 mils thick semi-permeable membrane bag 16, bothconfined within a porous copper shell 12 having a density of at least2.77, and having the following dimensions and specifications:

OUter diameter of dispenser 2.7 cm Wall thickness of porous shell 0.2 cmInner diameter of porous shell 2.3 cm Overall length 6.5 cm Externalvolume 37.2 cm Internal volume 25.3 cm Overall dispenser density 2 1.75Available membrane area 44.1 cm Active agent volume 20.2 cm Active agentdensity 1.2

Active agent: Approximately 60 percent tetracycline hydrochloridedispersed in 40 percent cocoa butter medium;

Osmotic solution: Saturated aqueous solution of K containing sufficientexcess solute in solid form to maintain solution saturated over a periodof at least 3 days;

Water permeable membrane: Cellulose diacetate,

with a degree of acetyl substitution of 2.4;

Active agent bag: Polyethylene;

is capable of deliverying 5 gm of the active drug per day, over a periodof 3 days, when administered to the rumen of a 500 pound calf, whereatit is retained, via the gastrointestinal tract.

Any of the drugs used to treat the body, both topical and systemic, canbe compartmentalized as the active agent in any of the osmoticdispensers of this invention. Drug is used herein in its broadest senseas including any composition or substance that will produce apharmacological or biological response.

Suitable drugs for use in therapy with the dispenser of the inventioninclude without limitation:

l. Protein drugs such as insulin;

2. Desensitizing agents such as ragweed pollen antigens, hay feverpollen antigens, dust antigen and milk antigen;

3. Vaccines such as smallpox, yellow fever, distemper, hog cholera, fowlpox, antivenom, scarlet fever, diptheria toxoid, tetanus toxoid, pigeonpox, whopping cough, influenzae, rabies, mumps, measles, poliomyletis,Newcastle disease, etc.;

4. Anti-infectives, such as antibiotics, including penicillin,tetracycline, chlortetracycline, bacitracin, nystatin, streptomycin,neomycin, polymyzin, gramicidin, oxytetracycline, chloramphenicol, anderythromycin; sulfonamides, including sulfacetamide, sylfamethizole,sulfamethazine, sulfadiazine, sulfamerazine, and sulfisoxazole;anti-virals including idoxuridine; and other anti-infectives includingnitrofurazone and sodium;

5. Anti-allergenics such as antazoline, methapyrilene,

chlorpheniramine, pyrilamine and prophenpyridamine;

6. Anti-inflammatories such as hydrocortisone, cortisone, hydrocortisoneacetate, dexamethasone, dexamethasone 2l-phosphate, fluocinolone,triamcinolone, medrysone, prednisolene, prednisolene 2lphosphate, andprednisolone acetate;

7. Decongestants such as phenylephrine, naphazoline, andtetrahydrozoline;

8. Miotics and anticholinesterases such as pilocarpine, eserinesalicylate, carbachol, di-isopropyl 'fluorophosphate, phospholineiodide, and demecarium bromide;

9 Mydriatics such as atropine sulfate, cyclopentolate,

homatropine, scopolamine, tropicamide, eucatropine, andhydroxyamphetamine;

l0. Sympathomimctics such as epinephrine;

ll. Sedatives and Hypnotics such as pentobarbital sodium, phenobarbital,secobarbital sodium, codeine,, (a-bromoisovaleryl) urea, carbromal;

l2. Psychic Energizers such as 3-(2-aminopropyl) indole acetate and3-(2-aminobutyl) indole acetate;

( l 3. Tranquilizers such as reserpine, chlorpromazine,

and thiopropazate;

l4. Androgenic steroids such as methyltestosterone and fluoxymesterone;

l5. Estrogens such as estrone, l7 B-estra'doil, ethinyl estradiol, anddiethyl stilbesterol;

l6. Progestational agents such as progesterone, megestrol, melengestrol,chlormadinone, ethisterone, norethynodrel, l9-norprogesterone,norethindrone, medroxyprogesterone and I7 a-hydroxyprogesterone;

l7. l-lumoral agents such as the prostablandins, for

example, PGE PGE and PGF l8. Antipyretics such as aspirin, sodiumsalicylate,

and salicylamide;

l9. Antispasmodics such as atropine, methantheline,

papaverine, and methscopolamine bromide;

20. Anti-malarials such as the 4-aminoquinolines, 8' aminoquinolines,chloroquine, and pyrimethamine;

2 l. Antihistamines such as diphenhydramine, dimenhydrinate,tripelennamine, perphenazine, and carphenazine;

22. Cardioactive agents such as hydrochlorothiazide,

flumethiazide, chlorothiazide, and trolnitrate;

23 Nutritional agents such as vitamins, essential amino acids andessential fats;

24. Anti-parkinsonism agents such as L-dopa, (L-3,4-

dihydroxyphenylalanine);

25. Investigative antihypotensive agents such as dopamine,4-(2-aminoethyl) pyrocatechol;

Other drugs having the same or different physiological activity as thoserecited above can be employed in osmotic dispensers within the scope ofthe present invention. Suitable mixtures of drugs can, of course, bedispensed with equal facility as with single component systems.

Drugs can be in various forms, such as uncharged molecules, componentsof molecular complexes, or non-irritating, pharmacologically acceptablesalts such as hydrochloride, hydrobromide, sulphate, phosphate, nitrate,borate, acetate, maleate, tartrate, salicylate, etc. For acidic drugs,salts of metals, amines, or organic -cations (e.g.,quaternary ammonium)can be employed. Furthermore, simple derivatives of the drugs (such asethers, esters, amides, etc.) which have desirable retention and releasecharacteristics but which are easily hydrolyzed by body pH, enzymes,etc., can be employed.

The amount of drug incorporated in the osmotic dispenser varies widelydepending on the particular drug, the desired therapeutic effect, andthe time span for which it takes the drug to be released. Since avariety of dispensers in a variety of sizes and shapes are intended toprovide complete dosage regimes for therapy for a variety of maladies,there is no critical upper limit on the amount of drug incorporated inthe dispenser.

The lower limit too will depend on the activity of the drug and the sametime span of its release from the dispenser. Thus is is not practical todefine a range for the therapeutically effective amount of drug to bereleased by the dispenser.

The motive force of the dispenser of this invention depends on theosmotic pressure generated by the solution of the osmotically effectivesolute contained in the semipermeable membrane or second bag 16, whichsolution exhibits an osmotic pressure gradient against water. Saidsolution is most preferably a saturated aqueous salt solution. Tomaintain the solution saturated and therefore to achieve a constantosmotic pressure throughout operation of the dispenser, the membrane orbag containing the solution also contains excess solute in solid form.Various osmotically effective solutes can be used. These includemagnesium chloride, magnesium sulphate, sodium chloride, potassiumsulphate, sodium carbonate, sodium sulphite, sodium sulphate, sodiumbicarbonate, potassium acid phthalate, calcium bicarbonate, potassiumacid phosphate, raffinose, tartaric acid, succinic acid, calciumsuccinate, calcium lactate, and magnesium succinate. The excess solidsolute can be in the form of dispersed particles or preferably in theform of a pellet. The solution can initially be a solution of the sameor of a osmoticaly effective solute different than the solid excesssolute.

Active agent release means, other than those heretofore mentioned, canbe a dispensing head which can take a variety of forms and can havevarying numbers of orifices. In one embodiment such a head is formed ofa relatively hard impact resistant material such as polyethylene,polypropylene, polystyrene, polymethylmethacrylate, or die cast metals.It is preferred that the construction of the said several bags and ofthe active agent release means be such that the osmotic driving pressuredeveloped is at least ten times greater than the back pressure generatedby the active agent formulation.

The osmotic dispenser can be fabricated in any convenient shape foreither physical insertion or implanation in the body, or foradministration via the gastrointestinal tract, or for introduction intoany desired environment. Dimensions of the device can thus vary widelyand are not of controlling importance. The lower limit of the size ofthe device is governed by the amount of the particular active agent tobe supplied to the environment to elicit the desired response, as wellas by the form of the dosage unit takes, for example, in cases ofspecific body uses, implantate, bolus, IUD, IVD, vaginal ring, uterinecapsule for fertility suppression, artificial gland, prosthesis,pessary, suppository, and the like. Likewise with respect to the upperlimit on the size of the device.

Thus, the invention provides, in an osmotic dispenser, a reliable meansfor releasing effective concentrations of active agent contained thereinto the body of a living organism, or to any other environment, at anosmotically controlled rate and over a prolonged period of time. Inaddition, prime advantages of the dispenser of the invention are that itis simple in construction and exhibits all of the practical benefits ofthe long-term continuous administration of various active agents both tohumans, animals, and into other environments, and that the active agentcontained therein will not exhibit the tendency to be leached therefrom.

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various modifications, changes, omissions, andsubstitutions can be made without departing from the spirit of theinvention. It is intended, therefore, that the invention be limited onlyby the scope of the following claims.

What is claimed is:

1. An osmotic active agent dispenser comprising (1) a porous housingmember affording free transport of water therethrough confining (2) afirst flexible bag of relatively impervious material containing anactive agent and provided with means for releasing the active agent tothe exterior of the dispenser, and (3) a second bag comprised ofmembrane material having controlled permeability to water, being atleast in part non-planar in configuration, and containing an osmoticallyeffective solute which, in solution, exhibits an osmotic pressuregradient against water, the said bags (2) and (3) being disposed withinthe said housing member (1) such that the bag (2) is collapsiblyresponsive to an increase in volume in the bag (3) via absorption ofwater therein, whereby as water flows into the dispenser in a tendencytowards osmotic equilibrium with its environment, active agent iscontinuously squeezed thereout at an osmotically controlled rate over aprolonged period of time.

2. The osmotic dispnser as defined by claim 1, wherein the active agentis selected from the group consisting of a drug and a bio-affectingcomposition.

3. The osmotic dispenser as defined by claim 1, wherein the active agentcontained therein is in the form of a semisolid formulation.

4. The osmotic dispenser as defined by claim 1, wherein the solutionexhibiting an osmotic pressure gradient against water is a saturatedaqueous salt solution.

5. The osmotic dispenser as defined by claim 4, wherein the saturatedsalt solution contains excess solute in solid form.

6. The osmotic dispenser as defined by claim 1, wherein the firstflexible bag (2) is comprised of a member selected from the grupconsisting of polyethylene, polyethylene terephthalate, polyvinylchloride, metal-foil polyethylene laminate, neoprene rubber, natural gumrubber and rubber hydrochloride.

7. The osmotic dispenser as defined by claim 1, wherein the second bag(3) is comprised of a member selected from the group consisting ofcellulose acetate, silicone rubber, polxurethane, natural rubber andhydrolyzed ethylene/vinyl acetate copolymer.

8. The osmotic dispenser as defined by claim 1, wherein the housingmember (1) is comprised of a member selected from the group consistingof perforated polystyrene, perforated polyethylene, perforatedpolypropylene, perforated polymethylmethacrylate,

perforated polyvinyl chloride, perforated reinforced epoxy resin,perforated sheet metal, metallic screen, perforated galvanized pipe,porous sintered brass tubing, porous styrene/acrylonitrile copolymer,and porous sintered polyethylene.

9. The osmotic dispenser of claim 2 wherein the said housing member (1)is in the configuration of an intravaginal device, ring-shaped, andadapted to be placed around the cervix.

10. The osmotic dispenser of claim 2 wherein the said housing member (1)is in the configuration of a veterinary bolus.

11. The osmotic dispenser as defined by claim 1, wherein the bags (2)and (3) are disposed in an essentially parallel configuration.

12. The osmotic dispenser as defined by claim 1, wherein the bags (2)and (3) are disposed in an essentially concentric configuration.

13. The osmotic dispenser as defined by claim 1, wherein the osmoticallyeffective solute is selected from the group consisting of magnesiumchloride, magnesium sulphate, sodium chloride, potassium sulphate,sodium carbonate, sodium sulphite, sodium sulphate, sodium bicarbonate,potassium acid phthalate, calcium bicarbonate, potassium acid phosphate,raffinose, tartaric acid, succinic acid, calcium succinate, calciumlactate and magnesium succinate.

14. The osmotic dispenser as defined by claim 1, further comprisingballast means to adjust the specific gravity of the device.

15. The osmotic dispenser as defined by claim 14 having a specificgravity of greater than 1.5.

16. The osmotic dispenser as defined by claim 1, further comprisingseparator means disposed between the said housing member (1) and thesaid second bag (3).

17. The osmotic dispenser as defined by claim 9, further comprising aplurality of duct-like fine tubule connections through the said housingmember (1) thereof.

18. An osmotic active agent dispenser comprising a shape retaininginjector divided into two compartments by a flexible diaphragm, one ofsaid compartments having an outer wall of relatively impervious materialcontaining an active agent and provided with means for releasing theactive agent to the exterior of the dispenser, and the other compartmenthaving an outer wall of membrane material having controlled permeabilityto water, being at least in part non-planar in configuration, andcontaining an osmotically efiective solute which, in solution, exhibitsan osmotic pressure gradient against water whereby as water flows intothe solute compartment in a tendency towards osmotic equilibrium withits environment, said diaphragm expands to continuously squeeze activeagent from the dispenser at an osmotically controlled rate over aprolonged period oftime.

2. The osmotic dispnser as defined by claim 1, wherein the active agentis selected from the group consisting of a drug and a bio-affectingcomposition.
 3. The osmotic dispenser as defined by claim 1, wherein theactive agent contained therein is in the form of a semisolidformulation.
 4. The osmotic dispenser as defined by claim 1, wherein thesolution exhibiting an osmotic pressure gradient against water is asaturated aqueous salt solution.
 5. The osmotic dispenser as defined byclaim 4, wherein the saturated salt solution contains excess solute insolid form.
 6. The osmotic dispenser as defined by claim 1, wherein thefirst flexible bag (2) is comprised of a member selected from the groupconsisting of polyethylene, polyethylene terephthalate, polyvinylchloride, metal-foil polyethylene laminate, neoprene rubber, natural gumrubber and rubber hydrochloride.
 7. The osmotic dispenser as defined byclaim 1, wherein the second bag (3) is comprised of a member selectedfrom the group consisting of cellulose acetate, silicone rubber,polxurethane, natural rubber and hydrolyzed ethylene/vinyl acetatecopolymer.
 8. The osmotic dispenser as defined by claim 1, wherein thehousing member (1) is comprised of a member selected from the groupconsisting of perforated polystyrene, perforated polyethylene,perforated polypropylene, perforated polymethylmethacrylate, perforatedpolyvinyl chloride, perforated reinforced epoxy resin, perforated sheetmetal, metallic screen, perforated galvanized pipe, porous sinteredbrass tubing, porous styrene/acrylonitrile copolymer, and poroussintered polyethylene.
 9. The osmotic dispenser of claim 2 wherein thesaid housing member (1) is in the configuration of an intravaginaldevice, ring-shaped, and adapted to be placed around the cervix.
 10. Theosmotic dispenser of claim 2 wherein the said housing member (1) is inthe configuration of a veterinary bolus.
 11. The osmotic dispenser asdefined by claim 1, wherein the bags (2) and (3) are disposed in anessentially parallel configuration.
 12. The osmotic dispenser as definedby claim 1, wherein the bags (2) and (3) are disposed in an essentiallyconcentric configuration.
 13. The osmotic dispenser as defined by claim1, wherein the osmotically effective solute is selected from the groupconsisting of magnesium chloride, magnesium sulphate, sodium chloride,potassium sulphate, sodium carbonate, sodium sulphite, sodium sulphate,sodium bicarbonate, potassium acid phthalate, calcium bicarbonate,potassium acid phosphate, raffinose, tartaric acid, succinic acid,calcium succinate, calcium lactate and magnesium succinate.
 14. Theosmotic dispenser as defined by Claim 1, further comprising ballastmeans to adjust the specific gravity of the device.
 15. The osmoticdispenser as defined by claim 14 having a specific gravity of greaterthan 1.5.
 16. The osmotic dispenser as defined by claim 1, furthercomprising separator means disposed between the said housing member (1)and the said second bag (3).
 17. The osmotic dispenser as defined byclaim 9, further comprising a plurality of duct-like fine tubuleconnections through the said housing member (1) thereof.
 18. An osmoticactive agent dispenser comprising a shape retaining injector dividedinto two compartments by a flexible diaphragm, one of said compartmentshaving an outer wall of relatively impervious material containing anactive agent and provided with means for releasing the active agent tothe exterior of the dispenser, and the other compartment having an outerwall of membrane material having controlled permeability to water, beingat least in part non-planar in configuration, and containing anosmotically effective solute which, in solution, exhibits an osmoticpressure gradient against water whereby as water flows into the solutecompartment in a tendency towards osmotic equilibrium with itsenvironment, said diaphragm expands to continuously squeeze active agentfrom the dispenser at an osmotically controlled rate over a prolongedperiod of time.